Maleimide adduct of levopimaric acid and derivatives



United States Patent 3,135,749 MALEIMEDE ADDUiZT 0F LEVOPEAARTC ACE) AND DERIVATIVES Raymond 0. Clinton, East Greenhush, and Andrew John Manson, North 'Greenhush, N.Y., assignors to terling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Apr. 14, 196i), Ser. No. 22,163

20 Claims. (Cl. zen-247.2

This invention relates to novel resin acid derivatives, and in particular is concerned with the maleimide adduct of levo-pimaric acid further substituted on the nitrogen atom by a tertiary-amino-lower-alkyl group, with certain transformation products thereof, and with processes for the preparation of the new compounds.

A preferred class of compounds of the invention comprises those having the formula (CO -alkyl), hydroxymethyl or carboxylic acyloxymethyl (CH O-acyl); X represents two hydrogen atoms (H or an oxygen atom (O); Y represents loweralkylene; and N=B represents tertiary-amino. In the carbolower-alkoxy groups the alkyl group preferably has from one to about six carbon atoms, and in'the carboxylic acyloxymethyl groups the acyl group preferably has irom one to about ten carbon atoms.

The compounds of the above Formula I can be named systematically as derivatives of phenanthro[l,2-c]pyrrolidine, viz.: 8 R 4b,8 dimethyl 12 isopropyll,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradccahydro 3,10aethenophenanthro[1,2-c] l (tertiary amino loweralkyl -2, '-X -pyrrolidine.

In the above general Formula I, R represents carboxy, carbo-lower-alkoxy, hydroxymethyl or carboxylic acyloxymethyl. The carbo-lower-alkoxy radicals have the formula -CO -lower-alkyl in which the lower-alkyl groups have from one to about six carbon atoms and can be straight or branched, thus including such groups as carhomethoxy, carbethoxy, carbopropoxy, carbo-isopropoxy, carbobutoxy, carbopentoxy, carbohexoxy, and the like. The carboxylic acyloxymethyl radicals have the formula --CH -O-acyl in which the carboxylic acyloxy groups are preferably derived from carboxylic acids having from one to about ten carbon atoms, and having a molecular weight less than about 200. Representative of the carboxylic acyloxymethyl radicals which can be present are lower-alkanoyloxymethyl radicals, e.g., formyloxymethyl, acetoxymethyl, propionyloxymethyl, butryloxymetyl, isobutyryloxymethyl, caproyloxymethyl, heptanoyloxy methyl, octanoyloxymethyl, trimethylacetoxymethyl, and the like; carboxy-lower-alkanoloxymethyl radicals, e.g., succinyloxymethyl (fi-carboxypropionyloxymethyl); cycloalkyl-lower-alkanoyloxymethyl radicals,

e.g., fi-cyclopentylpropionyloxymethyl, fl-cyclohexylpropionyloxymethyl, and the like; monocarbocyclic aroylmethyl radicals, e.g., benzoyloxymethyl, p-toluyloxymethyl, p-nitrobenzoyloxymethyl, 3,4,5-trimethoxyben-' zoyloxymethyl, and the like; monocarbocyclic aryl-loweralkanoyloxymethyl or alkenoyloxymethyl radicals, such as phenylacetoxymethyl, fl-phenylpropionyloxymethyl,

ice

cinnamoyloxymethyl, and the like; and monocarbocyclic aryloxy-lower-alkanoyloxymethyl radicals, such as pchlorophenoxyacetoxymethyl, and the like.

In the above general Formula I, N=B represents a tertiary-amino radical. By a tertiary-amino radical is meant a radical of the type YYN wherein Y and Y are both organic substituents so that the complete molecule to which it is attached is a tertiary-amine. The tertiary-amino radical is preferably basic and has a molecular weight less than about 200. Basic tertiary-amino radicals are those of the aliphatic or araliphatic type that impart to the molecules which contain them sufficient basicity so that the compounds readily form acid-addition salts with strong inorganic and organic acids. A particularly preferred group of tertiary-amino radicals are di-lower-alkylamino, for example, dirnethylamino, diethylamino, dibutylamino, methylethylamino, and the like; dicycloalkylamino in which the cycloalkyl has from 5 to 6 ring members, for example, dicyclopentylamino, dicyclohexylamino, bis(4-methylcyclohexy1)amino, and the like; N-(cycloalkyl)-N-lower-alkylamino in which the cycloalkyl has from 5 to 6 ring members, for example, N- (cyclohexyD-N-methylamino, N-(cyclopentyl)-N-ethylamino, and the like; polymethylenimino having from 5 to 7 ring members, for example, l-pyrrolidyl, l-piperidyl, hexamethylenimino and lower-alkylated derivatives thereof; 4-morpholinyl; l-piperazinyl; 4-hydrocarbon-1-piperazinyl in which the hydrocarbon has from 1 to 10 carbon atoms, for example, 4-methyl-l-piperazinyl, 4-phenyl-lpiperazinyl, and the like; di-(phenyl-lower-alkyl)amino, for example, dibenzylamino, bis(phenylethyl)amino, and the like; and N-(phenyl-lower-alkyl) -N-lower-alkylamino, for example, N-benzyl-N-methylamino N-phenylethyl-N-ethylamino, and the like. In the foregoing radicals, the term lower-alkyl stands for alkyl groups containing from one to about six carbon atoms.

In the above general Formula I, Y stands for a loweralklylene bridge, having from at least two to about five carbon atoms, in which the points of attachment to the remainder of the molecule are on different carbon atoms. In other words, the two nitrogen atoms of the molecule are separated by at least two carbon atoms. The loweralkylene bridge can be straight or branched and includes such groupings as CH CH CH CH(CH CH(CH )CH CH CH CH The compounds of Formula I wherein R represents carboxy or carbo-lower-alkoxy and Xrepresents O are prepared by causing maleopimaric acid or a lower-alkyl ester thereof to react with a tertiary-amino alkylamine of the formula H NY-N=B, wherein Y and N=B have the meanings given hereinabove. The process is carried out by heating approximately equimolar quantities of the reactants at a temperature between about 50 C. and 150 C. in an inert organic solvent, preferably with means for removing the water formed in the reaction.

The compounds of Formula I wherein R represents hydroxymethyl and X represents H are prepared by causing a compound of Formula I wherein R represents carboxy or carbo-lower-alkoxy and X represents 0 to react with lithium aluminum hydride. The'process is carried out by mixing the imido acid or ester with an excess of lithium aluminum hydride suspended in an inert organic solvent at a temperature between about 20 C. and C.

In order to obtain selectively reduced compounds of zenesulfonic acid, and the like.

I wherein R represents carboxy and X represents to the acid chloride by treating it with thionyl chloride, oxalyl chloride or a like reagent, and then causing the acid chloride to react with sodium borohydride. The acid chloride.

grouping is reduced to hydroxymethyl, but the imide carbonyl groups are not reduced by sodium borohydride. In order to obtain compounds of Formula I wherein R represents carboxy andX represents H the compounds wherein R represents hydroxymethyl and X represents H can be oxidized by methods known to oxidize primary alcohols to the corresponding carboxylic acids. Such methods comprise treating the alcohol with a sulfuricchromic acid mixture or with acid or alkaline permanganate solution at room temperature or below. If it is desired to obtain lower-alkyl esters of the resulting carboxy compounds, these can be obtained by conventional esterification procedures, for example, by reacting the acid and alower-alkanolin the'presence of a strong acid catalyst, by the action of a lower-alkyl halide on a salt of the acid,

from the acid chloride and a lower-alkanol, or, in the case of the methyl ester, by reacting the acid with diazomethane.

The compounds of Formula I wherein R represents carboxylic'acyloxymethyl are-prepared from the corresponding hydroxymethyl compounds by esterification. procedures, for example, by causing the hydroxymethyl compound to react with the appropriate acid anhydride or acid halide. The compounds of Formula I are basic in character,

those where X is 0 having one basic center and thosev where X is H having two basic centers. The compounds where X is 0 thus form rnono-acid-addition salts upon addition of strong acids and mono-quaternary ammonium salts upon addition of esters of strong acids. The compounds where X is H forminonoor di-acid-addition salts and mono? or di-quaternary ammonium salts. The salts are the full equivalent of the corresponding free bases insofar as their physiological properties are concerned. Both the free base and salt forms are considered to be one and the same invention.

. The acid-addition salts are'prepared by causing the free base to reactwith a strong inorganic or organic acid, usually in an inert solvent or reaction medium. Ex-

' amples of appropriate acids include hydrochloric, hydrobromic, sulfuric, phosphoric, citric, tartaric, quinic, ben- The quaternary ammonium salts of thecompounds of I the invention are prepared by causing a free base to react withan'ester of a strong inorganic or organic sulfonic acid, said ester preferably having a molecular weight less' than about 200. A particularlypreferred class of esters, because of their ready availability, are lower-alkyl, lowerbenzylchloride, o chlorobenzyl chloride,and the like. The reaction of the free base'and the quaternizing agent takes place :upon simple admixture of the components, preferably in the presence of an inert organic solvent, al-

though heating may be applied to accelerate the reaction.

-The acid-addition and quaternary ammonium salts preferablyhaveanions which are 'pharmacologically acceptable, that is, the anions do not appreciably increase the toxicity of the compound as a wholetoward animal organisms. .Such anions include, for example, the chlor de, bromide, iodide, sulfate or acidsulfate, methanesul fonate, benzenesulfonate, and the like.

Salts having toxic ion exchange reactions.

terizing derivatives of the freebase and serve as intermediates for non-toxic quaternary salts by conventional All acid-addition salts, regard less of the nature of the anions, are useful as intermediates in the purification of the free bases.

The compounds of the invention wherein R in Formula I above is carboxy are acidic as well as'basic in nature and will also form salts upon reacting them with strong bases, such as metal oxides or hydroxides, ammonia or organic amines. These salts are useful as characterizing derivatives of the free bases and/or intermediates in the preparation of esters (R is carbo-lower-alkoxy).

Pharmacological evaluation of the compounds of the invention has shown that they possess hypotensive' and coronary dilator activity when. administered to animal organisms in non-toxic doses. The new compoundsare thus useful in lowering blood pressure and alleviating the work load on the heart. The are administered either subcutaneously in the form of a sterile, isotonic aqueous solution or suspension, or orally in the form of tablets, powder or aqueous dispersions. The compounds are formulated in conventional fashion using an appropriate amount of the active ingredient or a salt thereof with ordinary pharmaceutical excipients.

The structure of the compounds of the invention was established by the mode of synthesis, by infrared spectral data, and by the fact that elementary analyses Were in agreement with the assigned structures.

The following examples will further illustrate the invention without the latter being limited thereby.

EXAMPLE 1 8 Carboxy-4b,8-Dimethyl-JZ-Isopropyl-I,2,3,4,4a,4b,5,6, 7,8,8a,9,10,10a T etradecahydro 3,]0a-Ethenophenandione [1; R is COOH, X is O, Y. is CH CH N=B is N(C H Z-diethylaniinoethylamine (7.0 g., 0.06 mole) was added to a solution of 24.0 g. (0.06 mole) of maleopimaric acid in 300 ml. of benzene, and the mixture was refluxed for The reaction mixture was then cooled and the benzene removed in vacuo on a steam bath. The residue was crystallized from 200 ml. of ethyl acetate to give two crops of crystalline product, 14.80 g, MP. l70172 C. (uncorr.) and 5.95 g., M;P. l67l71 C. (uncorr.) The total product wasrecrystallized from acetone and again from ethyl acetate and dried at 85 C. in vacuo for six hours to give 8-carb'oxy-4b,8-

tetradecahydro 3,l0a-ethenophenanthro[1,2-c] -1-(2-diethylaminoethyl) 2Z5 pyrrolidinedione, M.P. 168.2-

' 169.450 (corn), [q] =,+17.6:0.3 (1% inchloroform); infrared maxima at 5.65 and 5.88

Analysis.--Calcd. for C I-1 N 0 C, 72.25; H, 9.30;. 0, 12.83.

8-carboxy-4b,8-dimethyl 12-isopropyl 1,2,3,4,4a,4b,"

Found: C, 72.35; H, 9.65; O, 12.80.

' 5,6,7,8,8a,9,10,l0a-tetradecahydro-3,10a ethenophenanthro[1,2-c]-i'-(2-diethylaminoethyl) 2,5'. pyrro1idine-- .dione is obtained in the form of its hydrofiuoride, hydrobromidc, 'hydriodide, sulfate (or bisulfate), phosphate (or acid phosphate), acetate, tartrate (or bitartrate); lactate, citrate (or'acid'citrate), benzenesulfonate, ethaneulfonate, methiodide, allobromide or benzochloride salt, when contacted, respectively, with hydrofluoric acid,

hydrobromic acid, hydn'odic acid, sulfonic acid, phosphoric acid, acetic acid, tartaric acid, lactic 'acid,.citric acid, ben zenesulfonicacid, ethanesulfonic acid, methyl iodide, allyl bromide or benzyl chloridei 8-carboxy-4b,8-dimethyl 12-isopropyl -"1,2,3,4,4a,4b, 5,6,7,8,8a,9,l0,l0a-tetradecahydro-3,10a ethenophenanthro[l,2-c]+1'-(Z-diethylaminoethyl)- 2',5 pyrrolidine- I drone in the form of its hydrofiuoride salt can be'con verted'to the hydrochloride salt by passing an aqueous 5 solution of the former over an ion-exchange resin saturated with chloride ion.

8-carboxy-4b,8-dimethyl l2-isopropyl 1,2,3,4,4a,4b, 5,6,7,8,8a,9,10,10a-tetradecahydro-3,10a ethenophenanthro[l,2-c]-1-(2-diethylaminoethyl) 2',5 pyrrolidinedione reacts in aqueous solution with sodium hydroxide, potassium hydroxide, calcium chloride or silver nitrate to give, respectively, the sodium, potassium, calcium or silver salt of said 8-carboxy compound. Said silver salt can be caused to react with methyl iodide, ethyl iodide, isopropyl bromide or isoamyl bromide to give, respectively, the methyl ester, ethyl ester, isopropyl ester'or isoamyl ester of 8-carboxy-4b,8-dimethyl-l2-isopropyll,2,3,4,4a,4b,5,6,7,8,8a,9,l0,10a tetradecahydro 3,10aethenophenanthro[1,2 c] 1 (2 diethylaminoethyl)- 2,5-pyrrolidinedione.

8-carboxy-4b,8-dimethyl l2-isopropyl 1,2,3,4,4a,4b, 5,6,7,8,8a,9,10,10a-tetradecahydro-3,10a ethenophenanthro[1,2-c]-1-(2-diethylaminoethyl) 2.,5' pyrrolidinedione in the form of its hydrochloride salt was found to have a minimum effective hypotensive dose of about 0.01 mg./ kg. of body weight when injected subcutaneously into renal hypertensive rats and measured by the photoelectric foot method of Kersten et al., J. Lab. Clin. Med. 32, 1090 (1947). The intravenous toxicity (LD in the mouse was found to be 80:7.0 mg./kg..

EXAMPLE 2 8-carboxy-4b,8-dimethyl 12-isopropyl 1,2,3,4,4a,4b, 5,6,7,8,8a,9,10,10a-tetradecahydro-3,10a ethenophenanthro[l,2 c] 1' [2 (4-morpholinyl)ethyl]-2'-,5-pyrrolidinedione [1; R is COOH, X is O, Y is CH CH N=B is N(CH O] was prepared from 7.31 g. of 2-(4- morpholiriyhethylamine and 18.67 g. of maleopimaric acid in 250 ml. of benzene according to the manipulative procedure described above in Example 1. There Was thus obtained 18.0 g. of 8-cmboxy-4b,8-dimethyl-l2-isopropyl 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro- 3,la-ethenophenanthro[1,2-c]-1 [2 (4- morpholinyl) ethyl] 2',5 pyrrolidinedione, M.P. 203.0-204.0 C. (corn), [a] =32.9 i0.2 (1% in chloroform) when recrystallized from ethyl acetate and dried at 60 C. for forty-eight hours in vacuo.

Analysis.Calcd. for C H N O C, 70.28; H, 8.65; N, 5.46; O, 15.60. Found: C, 70.33; H, 8.38; N, 5.48; O, 15.30.

EXAMPLE 3 8-carboxy-4b,8-dimethyl 12-isopropyl 1,2,3,4,4a,4b, 5,6,7,8,8a,9,10,l0a-tetradecahydro3,l0a ethenophenanthro[1,2-c]-1'-(3-hexamethyleniminopropyl) 2',5' pyrrolidinedione [1; R is COOH, X is O, Y is CH CH CH N=B is N(CH was prepared from 25.78 g. of 3- hexamethyleniminopropylamine and 60.08 g. of maleopimaric acid in 600 ml. of benzene according to the manipulative procedure described above in Example 1. There was thus obtained 68.4 g. of 8-carboxy-4b,8-dimethyl 12 isopropyl- 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10atetradecahydro 3,10a ethenophenanthro[1,2 c] 1'- (3-hexamethyleniminopropyl) 2',5' pyrrolidinedione, M.P. 197.6-20l.8 C. (corr.), [a] =24.8 :01 (1% in chloroform) when recrystallized from ethyl acetate and dried at 6572 C. for nineteen hours in vacuo.

Analysis.-Calcd. for C H N O C, 73.56; H, 9.35; N, 5.20. Found: C, 73.43; H, 9.20; N, 5.11.

8-carboxy-4b,8-dimethyl lZ-isopropyl l,2,3,4,4a,4b, 5,6,7,8,8a,9,10,l0a-tetradecahydro-3,l0a ethenophenantl1ro[1,2-c] -1-(3-hexamethyleniminopropyl) 2,5' -pyr rolidinedione in the form of its hydrochloride salt was found to have a minimum efiective hypotensive dose of about 0.01 mg./kg. of body Weight when injected subcutaneously into renal hypertensive rats and measured by the photoelectric foot method of Kersten et al., loc. cit. The intravenous toxicity (ALD in the mouse was found to be 120 mg./kg.

6 EXAMPLE 4 8-carboxy-4b,8-dimethyl 12-isopropyl l,2,3,4,4a,4b, 5,6,7,8,8a,9,10,l0a-tetradecahydro-3,l0a ethenophenanthro[1,2-c] 1' (3 dimethylaminopropyl) 2,5' pyrrolidinedione [1; R is COOH, X is O, Y is CH CH CH N=B is N(CH was prepared from 11.24 g. of 3- dimethylaminopropylamine and 40.05 g. of maleopimaric acid in 500 ml. of benzene according to the manipulative procedure described above in Example 1. The product was leached with hot ethyl acetate and the ethyl acetate insoluble portion was recrystallized from ethanol and dried for eighteen hours at 50 C. in vacuo to give 35.72 g. of 8-carboxy-4b,8-dimethyl-12-isopropyl-1,2,3,4,4a,4b, 5,6,7,8,8a,9,10,l0a-tetradecahydro-3,10a ethenophenantl1ro[ 1,2-c] -1'-(S-dimethylaminopropyl) -2',5-pyrrolidinedione, M.P. 237.4241.0 C. (corn), [a] =2l.8 (1% in chloroform).

Analysis.Calcd. for C H N O N, 5.78; O, 13.21. Found: N, 5.72; O, 13.20.

8-carboxy-4b,8-dimethyl 12-isopropy1 1,2,3,4,4a,4b, 5,6,7,8,8a,9,10,l0a-tetradecahydro-3,l0a ethenophenam thro[1,2-c] 1 (3 dimethylaminopropyl) 2,5 pyrrolidinedione in the form of its hydrochloride salt was found to have a minimum efiective hypotensive dose of about 0.10 mg./kg. of body Weight when injected subcutaneously in renal hypertensive rats and measured by the photoelectric foot method of Kersten et al., 10c. cit. The intravenous toxicity (ALD in the mouse was found to be 125 rug/kg.

EXAMPLE 5 8 carboxy-4b,8-dimethyl-12-isopropyl-1,2,3,4,4a,4b,5, 6,7,8,8a,9,10,10a tetradecahydro 3,10a-ethenophenanthro[1,2 c] 1-[3-(l-pyrrolidyl)propyl]-2',5-pyrrolidinedione [1; R is COOH, X is O, Y is CH CH CH N=B is N(CH was prepared from 8.08 g. of 3-(1- pyrrolidyl)propylamine and 24.03 g. of maleopimaric acid in 300 ml. of benzene according to the manipulative procedure described above in Example 1. The crude product was dissolved in about 1 liter of chloroform, hot ethyl acetate was added until the total volume was 1600- 1800 m1., and the solution was then concentrated to about 800900 ml. The precipitated product was collected by filtration and dried in vacuo for about twenty hours at 6870 C. and for sixteen hours at 97 C. to give 23.68 g. of 8-carboxy-4b,8-dimethyl-12-isopropyl-1,2,3,4,4a,4b, 5,6,7 ,8,8a,9,10,10a-tetradecahydro 3,10a ethenophenanthro [1,2 c]-l-[3-(1 pyrrolidyDpropyl]-2',5-pyrrolidinedione, M.P. 2366-2506 C. (corn), [a] =23.3 (1% in chloroform). I

Analysis.-Calcd. for C I-I N O.,: C, 72.90; H, 9.08; N, 5.49. Found: C, 72.88; H, 9.21; N, 5.61.

EXAMPLE 6 8 carboxy-4b,S-dimethyl-lZ-isopropyl-1,2,3,4,4a,4b,5, 6,7,8,8a,9,l0,10a tetradecahydro 3,10a-ethenophenanthro[1,2 c] 1'-[2-(1-piperazinyl)ethyl]-2',5'-pyrrolidinedione [1; R is COOH, X is O, Y is CH CH N=B is N(CH NH] was prepared from 8.06 g. of 2-(l-piperazinyl)ethylamine and 24.03 g. of maleopimaric acid in 500 ml. of benzene according to the manipulative procedure described above in Example 1. The crude product was recrystallized by dissolving it in hot acetic acid, adding hot benzene and concentrating the solution. There was thus obtained 16.4 g. of 8-carboxy-4b,8-dimethyl-12- isopropyl 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a-tetradecahydro-3, 10a ethenophenanthro 1,2-c] -1'- [2- l-piperazinyl) ethyl] 2,5 pyrrolidinedione, M.P. 264.2266.4 C. (corn), [a] =26.7 (in 2 equivs. of 0.1 N HCl) after drying at 100-110 C. for sixty hours over phosphorus pentoxide.

Analysis.Calcd. for C3QH45N304: N t t 1 N m 5.47. Found: Na m 8.03; Nw 5.25.

7 EXAMPLE 7 8 carboxy-4b,S-dimethyl-1Z-isopropyl-1,2,3,4,4a,4b,5, 6,7,8,8a,9,10,10a tetradecahydro 3,10a-ethenophenan thro[1,2 c]-1'- [2-(4-phenyl-1-piperazinyl) ethyl] -2,,5 pyrrolidinedione [1; R is COOH, X is O, Y is CH CH N=B is N(CH NC H was prepared from 6.62 g. of 2-(4-phenyl-1-piperazinyl)ethylamine and 12.02 g. of

l maleopimaric acid in 250 ml. of benzene according to the manipulative procedure described above in Example 1. The product Was recrystallized from ethyl acetate and dried at 105110 C. in vacuo for sixteen hours to give 12.88 g. of 8carboxy-4b,8-dimethyl-l2-isopropyl-1,2,3,4, 4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,la-ethenophenanthro 1,2 fc] -1'- [2- (4-phenyl-1-piperazinyl ethyl] 2',5'-pyrrolidinedione, M.P. 255.0-257.8 C. (corr.), [a] =-32.O (1% in pyridine).

Analysis;'-Calcd for C36H49N304I Na t Nflyasic), 4.77. Found: Na Nw 4.73.

EXAMPLE 8 8 carbomethoxy 4b,8-dimethyl-12-isoprcpyl-1,2,3,4, 4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,10a-ethanophenanthro[l,2 c] 1'-(Z-diethylaminoethyl)-2;5'-pyrrolidinedione [1; R is (300C11 X is O, Y is CH CH N=B is N(C H can be prepared by replacing the maleopimaric acid in Example 1 by a molar equivalent amount of the methyl ester of maleopimaric acid. 7 The same product is obtained by'causing the compound of Example 1 to react with diazomethane. 7

EXAMPLE 9 8 carboxy-4b,8-dimethyl12-isopropy1-1,2,3,4,4a,4b,5, 6,7,8,8a,9,10,10a tetradecahydro 3,10a-ethenophenanthro[l,2 c] 1' (2 Nmethylethylaminoethyl)-2',5-pyrrolidinedione [1; R-is COOH, X is O, Y is CH CH N=B is N(CH )C H5)] can be prepared by replacing the 2-diethylaminoethylamine in Example 1 by a molar equivalent amount of Z-N-rnethylethylaminoethylarnine. 7

EXAMPLE l is N(C H can be prepared by replacing theVZ-diethylaminoethylamine in Example l by' a molar equivalent amount of 2-di-n-hexylaminoethylamine.

EXAMPLE '12 V 8 carboxy-;4b,8-dimethyl-l2-isopropyl-1,2,3,4,4a,4b,5, 6,7,8,8a,9,10, 10a tetradecahydro 3,10a-ethenophenanthro[1,2 c] 1'-(Z-dicyclohexylarhinoethyl)-2,5'-pyrrolidinedione" [1; R is COGH, X is O, Y is CH CHQ, N=B is N(C H can be prepared by replacing the 2-diethylaminoethylami ne in Example 1 by a molar equivalent amount'of 2-dicyclohexylaminoethylamine.

' EXAMPLE 13 6,7,8,8a,9 10,10a tetradecahydro 3,10a-ethenophenanthro[1,2 1 c] 1'- [Z-bis(4-methylcyclohexyl)aminoeth yl]-2',5'-pyrrolidinedione [1; R is. COOH; X is O, Y is 'CH CH' N=B is N(C H CH -4) can be prepared a by replacing the Z-diethylaminoethylarnine in Example 1 by a molar equivalent amount of 2-bis(4-rnethylcyclohexyl) aminoethylamine.

ethylaminoethylamine inExample 1 by a molar 8 EXAMELE 1 8 carboxy-4b,8-dimethyl-12-isopropyl-1,2,3,4,4a,4b,5, 6,7,8,8a,9,10,10a tetradecahydro 3,10a-ethenophenanthro[1,2 c] 1'-(2-N methylcyclohexylaminoethyl)-2,

5'-pyrrolidinedione [1; R is COOH, X is O, Y is CH CH N=B is N(CH (C H can be prepared by replacing the Z-diethylaminoethylamine in Example 1 by a molar amine.

equivalent amount of 2-N-methylcycloheXylaminoethyl- EXAMPLE l5 8,carboxy,-4b,8 dimethyl-12-isopropyl-1;2,3,4,4a,4b,5, 6,7,8,8a,9,10,10a-tetradecahydro-3,10a ethenophenanthro [1,2-c] -1 [2- l-piperidyl ethyl] -2',5'-pyrrolidinedione [1; R is COOH, X is O, Y is CH CH N=B is N(CH can be prepared by replacing the Z-diethylaminoethyl amine in Example 1 by a molar equivalent amount of 2- 1-piperidyl)ethylamine.

7 EXAMPLE 16 8 carboxy-4b,8 -dimethyl-12-isopropyl-1,2,3,4,4a,4b,5, 6,7,8,8a,9,10, IOa-tetradecahydro 3,10a-ethenophenanthro [1,2-c] -1 '-[Z-(Z-methyl-l-pyrrolidyl) ethyl] 2',5-pyrrolidinedione [1; R 'is COOH, X is O, Y is CH CH N=B is Z-methyl-l-pyirolidyl] can be prepared by replacing the Z-diethylaminoethylamine in Example 1 by a molar equivalent amount of 2-(2-methyl-1-pyrrolidyl)ethylaniine.

EXAMPLE 17 6,7,8,8a,9,10,10a-tetradecahydro-3,10a ethenophenanthro [1,2-c]-1-[2-(4::nethyl-1-piperazinyl)ethyl] -2',5' pyrrolidinedione [1; R is COOH, X is O, L is CH CH N=B is N(CH NCH can be prepared by replacing the 2- diethylaminoethylamine in Example 1 by a molar equivalent amount of 2-(4-methyl-1-piperazinyl)ethylamine.

EXAMPLE 18 8l-carboxyl-4b,8-dimethyl-12-isopropyl 1,2,3,4,4a,4b,5,

6,7,8,8a,9,10,10a-tetradecahydro 3,10a-ethenophenanthro [1,2-c]-1"-(Z-dibenzylaminoethyl)-2,5' pyrrolidinedione N(CH C H can be prepared by replacing the 2-di-' equivalen amountof Z-dibenzylaminoethylamine. 7

EXAMPLE l9,

8-carboxy-4b,8-dimethyl-12-isopropyl 1,2,3,4,4a,4b,5, 6,7,8,8a,9,10,10a tetradecahydro-3,IOa-ethenophenanthro lidinedione [1; R is COOH, X is O, Y is CH CH N=B V is LN(CH 'CH C H can be prepared by replacing the Z-diethylaminoethylarhine in Example 1 by a molar equivalent amount of 2-bis(2-phenylethyl)aminoethyl-' amine.

EXAMPLE 20 p 8-carboxy 4b,8-dimethyl-1Z-isopropyl-l,2,3,4;4a,4b,5, 6,7,8,8a,9,10,10a-tetradecal1ydro-3, 10a ethenophenanthro [1,2-01-1 (Z-N-methylbenzylaminoethyl) 2,5'pyrrolidinedione [1; R is COOH, X' is 0, Y is CH CH N=B is N(CH (CH C H5)] can be prepared'by replacing the 2-diethylaminoethylamine in Example 1 by a molar equivalent amount of Z-N-rnethylbenzylaminoethylamine. 7

EXAMPLE 21 8-carboxy-4b,8-dimethyl-12-isopropyl 1, 2,3,4,'4a,4b,5 s

6,7,8,8a,9,10,10a tetradecahydrO-S,10a-ethenophenanthro lidinedione [1; R is COOH, X is 0, Y is CH(CH )CH N=B is N(CH can be prepared by replacingthe 2- 8-carbo'xy 4b,8-dimethyl-12-isopropyl-1,2,3,4,4a,4b,5,-

diethylaminoethylamine in Example 1 by a molar equivalent amount of Z-dimethylamino-l-methylethylamine.

EXAMPLE 22 8-carboxy-4b,8,dimethyl-12-isopropyl 1,2,3,4,4a,4b,5, 6,7,8,8a,9,l0,10a-tetradecahydr-3,10a ethenophenanthro [1,2-c]-l'-(2-dimethylaminopyropyl) 2',5' pyrrolidinedione [1; R is COOH, X is O, Y is CH CH(CH N'=B is N(CH can be prepared by replacing the Z-diethylaminoethylamine in Example 1 by a molar equivalent amount of Z-dimethylaminopyropylamine.

EXAMPLE 23 8-carboxy-4b,8-dimethyl-l2-isopropyl 1,2,3,4,4a,4b,5, 6,7,8,8a,9,10,10a tetradecahydro-3,lOa-ethenophenanthro [1,2-c]-1'-(4-dimethylaminobutyl) 2',5'-pyrrolidinedione [1; R is COOH, X is O, Y is CH 'CH CH CH N B is N(CH can be prepared by replacing the 2-diethylaminoethylamine in Example 1 by a molar equivalent amount of 4-din'iethylaminobutylamine.

EXAMPLE 24 8-carboxy-4b,8-dimethyl-12-isopropyl l,2,3,4,4a,4b,5, 6,7,8,8a,9,10,l0a tetradecahydro-3,IOa-ethencphenanthro [1,2-c]-1'-(5-dimethylaminopentyl) 2',5 pyrrolidinedione [1; R is COOH, X is O, Y is CH CH CH CH CH N=B is N(CH can be prepared by replacing the 2 diethylaminoethylamine in Example 1 by a molar equivalent amount of S-dimethylaminopentylanfine.

EXAMPLE 25 EXAMPLE 26 4!),8-Dimethyl-S-Hydroxymethyl-12-lsopropyl 1,2,3,4,4a

4b,5,6,7,8,8a,9,10,10a Tetradecahydr0-3,10a thenophenanzhr0[1,2-c] 1'-(2 Diethylaminoethyl)Pyrrolidine 1; R is cn on, x is in, Y is cn cn N=B is N(C2H5)2] 8-carboxy-4b,8-dimethyl-l2-isopropyl 1,2,3,4,4a,4b,5, 6,7,8,8a,9,10,10a-- tetradecahydro-B', l Oa-ethenophenanhro [1,2-c]-1-(2-diethylaminoethyl) 2',5 pyrrolidinedione (Example 1) (20.92 g., 0.042 mole) was placed in the thimble of a Soxhlet extraction apparatus and leached into a suspension of 8.0 g. (0.21 mole) of lithium aluminum hydride in 800 ml. of anhydrous ether. After sixteen hours the starting material had been completely dissolved, and the excess lithium aluminum hydride was decomposed by the addition of saturated Rochelle salt solution in a nitrogen atmosphere. The mixture was filtered and the solid material Washed with water, methanol and ether. The filtrate and washings were separated into organic and aqueous layers, and the organic layer was washed with water, dried and concentrated in vacuo. The residue starting at 243.0 C (corr..), [a] =+l.84:l:0.2 (1% in ethanol) when recrystallized twice from a methanolether mixture.

Analysis.Calcd. for C3gH52N2O.2HC1: C, 68.02; H, 10.26; C1, 13.39. Found: C, 68.05; H,10.22; C1, 13.40.

The same product is obtained by lithium aluminum hy' dride reduction of 8-carbomethoxy-4b-S-dimethyl-12-isopropyl-l,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro- 3,10a-ethenophenanthro l,2-c]-1-(2 diethylaminoethyl) 2',5'-pyrrolidinedione (Example 8).

4b,8-dimethyl-S-hydroxymethyl-12 isopropyl 1,2,3,4, 4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,10a ethenophenanthro-[ 1,2-c] -1-(2-diethylaminoethyl)pyrrolidine is obtained in the form of its hydrofluoride, hydrobromide, hydroiodide, sulfate (or bisulfate), phosphate (or acid phosphate), acetate, tartrate (or bitartrate), lactate, citrate (or acid citrate), benzenesulfonate, ethanesulfonate, methiodide, allobromide or benzochloride salt, when contacted, respectively, with hydrofluoric acid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, lactic acid, citric acid, benzenesulfonic acid, ethanesulfonic acid, methyl iodide, allyl bromide or be'nzyl chloride.

4b,8-dimethyl 8 hydroxymethyl 12 isopropyl-1,2,3, 4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro-3,10a-ethenophenanthro 1,2-c] -1'-(2-diethylaminoethyl) pyrrolidine in the form or" its hydrofiuoride salt can be converted to the hydrochloride salt by passing an aqueous solution of the former over an ion-exchange resin saturated with chloride ion.

A solution of 6.17 g. of 4b,8-dimethyl-S-hydroxymethyl- 12-isopropyl 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro-3,l0a-ethenophenanthro[1,2-c]-1'-(2 diethylaminoethyl)pyrrolidine and an excess of methyl iodide in methanol solution was refluxed for three hours. The crystalline product which separated upon cooling was collected and recrystallized from acetone to give 4.80 g. of the monomethiodide salt, M.P. 192200 C. (uucorr.). A sample when purified by several recrystallizations from acetone had the MP. 201.8203.6 C. (corr.), =5.6 (1% in ethanol).

Analysis.-Calcd. for C H IN O: C, 62.19; H, 9.26; I, 21.20. Found: C, 62.51; H, 9.00; I, 21.01.

The mother liquors from the recrystallizations of the above monomethiodide were taken to dryness, the residue dissolved in 50 ml. of ethanol, 5 ml. of methyl iodide added, and the mixture refluxed for eighteen hours. The reaction mixture was evaporated to dryness, the residue recrystallized several times from acetone, and the product dried at 90 C. for eight hours in vacuo to give the dimethiodide salt of 4b,8-dimethyl-8-hydroxymethyl-12-isopropyl-1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro-3, 10a ethenophenanthro[1,2-c] 1' (Z-diethylaminoethyl)pyrrol idine, M.P. 222-236 C. (uncorr.).

Analysis.-Calcd. for c n oir r i 134.27. 1 Found:

was recrystallized from ether togive 14.41 g. of 4b, 8-

dimethyl-S-hydroxymethyl-12-isopropyl 1,2,3,4,4a,4b,5, 6,7,8,8a,9,10,10a tetradecahydro-S,10a-ethenophenanmo [1,2-c] -1'-(2 diethylaminoethyl)pyrrolidine, M.P. 116- 122 C. (uncorr.). A sample (4.00 g.) of the free base was dissolved in 95 m1. of ether and 5 ml. of methanol, and the solution was cooled to 0 C. There was then added 7.26 ml. of 2.66 molar ethereal hydrogen chloride. After standing for two hours in an ice bath there separated 4.64 g. of the dihydrochloride salt, MP. indefinite 4b,8-dimethyl 8 hydroxymethyl 12 isopropyl-1,2, 3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,10a-ethenophenanthro[1,2-c] 1 (2 diethylaminoethyl)pyrroli dine can be caused to react with acetic anhydride, propionic anhydride, caproyl chloride, succinic anhydride, 5- cyclopentylpropionyl chloride, benzoyl chloride,p-nitrobenzoyl chloride, 3,4,5-trimethoxybenzoyl chloride, phenylacetyl chloride, cinnamoyl chloride, or p-chlorophenoxyacetyl chloride, by heating in thepresence of pyridine, to give, respectively, 8-acetoxymethyl-,- 8-propionoxymethyl-, 8-caproyloxymethyl-, 8 (js-carboxypropionoxy)methyl-, 8-(,B-cyclopentylpropionoxy)methyl-, 8-benzoyloxymethyl-, 8-(p-nitrobenzoyloxy)'methyl-, 8-(3,4,5-trimethoxybenzoyloxy)methyl-, 8-phenylacetoxymethyl-, 8-cinnamoyloxymethyl-, or 8-(p-chlorophenoxyacetoxy)methyl-4b,8- dimethyl-12-isopropyl 1,2,3,4,4a,4b56,7,8,821,9,10,10atetradecahydro 3,1021 ethenophenanthro[l,2-c]-1-(2- diethylaminoethyl) pyrrolidine.

1 1 EXAMPLE 27 4b,8-Dimethyl-8-Hydroxymezhyl l2 lspr0p yl-1,2,3,4,'

4a,4b,5,6,7,8,8a,9,1 0,1 Oa-Tetradecahydro 3,1011 Ethen0phenanthr0[1,2 61-1 '-[2 (4 MorpholinyDEthyl] Pyrrolidine [I; R is CH OH, X is H Y is CH2CH N B is 2)4 product was collected and converted to the dihydrochloride salt with excess ethereal hydrogen chloride. The dihydrochloride salt was recrystallized from a methanol-ether mixture [M.P; 206-232 C. (uncorr.)] and then converted to the free base 'by treating it with 5% aqueous potassium hydroxide solution. The free base was extracted with ether, and the ether extracts were washed with water and saturated sodium chloride solution and concentrated. The residue was recrystallized from ethyl acetate and dried at 50 C. for four hours in vacuo over phosphorus pentoxide to give 3.27 g. of 4b,S-dimethyl-S-hydroxymethyl-12-isopropyl l,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro- 3,IOa-ethenophenanthro[1,2-0] 1' [2(4-morpholinyl) ethylJpyrrolidine, M.P. 89.4-94.0 C. (corn), [M =13.8 (1% inchloroform). Analysis.'-Calcd. for CgQHso N 0 C, 76.54; H, 10.71; 0, 6.80. Found: C, 76.74; H, 10.90; 0, 6.83.. "4b,'8 dirnethyl --8 hydroxymethyl 12 isopr'opyL '1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,1021- ethenoph'enanthro[l,2 c] l [2-(4-morpholinyl)ethyl] pyrrolidine in the form of its dihydrochloride salt was found to have a minimum effective hypotensive dose of about 0.10 mg./kg. of body weight when injected subcutaneously into renal hypertensive rats and measured by the photoelectric foot method of Kersten et al., loo. cit.:

EXAMPLE 28 4b,8 dimethyl 8 hydroxymethyl 4 12 isopropyl- 1,2,3,4,4a,4b;5,6,7,8,8a,9,10,10a tetradecahydro 3,10aethenophenanthro[1,2-c]' 1 (3 hexamethylenimino-- propyl)pyrr0lidine [1; R is CH OH, X is H Y is [1,2-c] 1 (3 hexamethyleniminopropyl) 2,5' pyrrolidinedione (Example 3) and 9.49 g. of lithium aluminum hydride in 1500 ml. of ether according to the manipulative procedure described above in Example 2 6. The

crude product was treated with excess ethereal hydrogen chloride to give 22.0 g; of 4b,8-dimethyl-8-hydroxymethyl- 12 isopropyl 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,10a ethenophenanthro[1,2-c]-1'-(3 hexa- 4a,4b,5,6,7,8 ,8a,9,10,10a-tetradecahydro 3,10a'-' ethenophenanthro[1,2-c] 1' (3-dimethylarninopropyl)pyrrolidine in the. form of its diphosphate salt was found to have V The intravenous toxicity (ALD in the mouse was found to be 22 mg./kg.

EXAMPLE 29 4b,8 dimethyl 8 hydroxymethyl 12 isopropyl- 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,10a-

ethenophenanthro[1,2 c] 1' (3 'dimethylaminopropyl)pyrrolidine [1; R is CH OH, X is' H Y is CH CH CH N=B is N(CH was prepared from 12.12 g. of 8 carboxy 4b,8 dimethyl 12 isopropyll,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,10a-. ethenophenanthro[1,2 c] 1 (3 dimethylaminopropyl)-2,5-pyrrol idinedione (Example 4). and 4.74 g. of

lithium aluminum hydride in 600 mLof tetrahydrofuran according to the manipulative procedure described above in Example 27. The total product was dissolved in 300 ml. of methanol, and 35-40 ml. of methanol containing 5.8 g. of phosphoric acid'wasadded. The solution was concentrated to a volume of 200 ml., 200 ml. of isopropyl alcohol was added, and the solution was further concentrated until crystallization began. The product was collected, recrystallized from a .methanol-isopropyl alcohol mixture and dried for sixteen hours at C.

in vacuo over phosphorus pentoxide to give 12.33 g. of

4b,8 dimethyl .8 hydroxymethyl 12 isopropyl- 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,10aethenophenanthro[1,2 c] 1' (3 dimethylaminopropyl)pyrrolidine in the form of its diphosphate salt, M.P." 216.6-221.4 C. (corn), [u] {-1.0 (1% in rnethanol).

to be 34:2.0 rug/kg.

4b,S-dimethyl-8-hydroxymethyl 12 isopropyl-1,2,3,4,

a coronary dilator activity 2-4 times that of papaverine when measured on the isolated rabbit heart by the method of Luduena et a1.,.J. Am; Pharm. Assoc., Sci. Ed.,44,

ass- 1955 EXAMPLESO I 4b,8-diniethyl-S-hydroxymethyl 12 isopr0pyl-1,2,3,4, 4a,4b,5,6,7,8,8a,9,10,l0a tetradecahydro 3,10a' etheno-r phenanthroELZ-cl- 1' [3- 1-pyrro1idy1)propyl]pyrrolidine [1; R is CH OH, X is H2, Y is, CH CH CH N B i 'is N(CH was prepared from 15.32 'g. of-.8-.carbo'xy-' 4b,8-dimethyl -,12 isopropyl- 1,2,3,4,4a,4b,5,6,7,8,8a,9,

methyleniminopropyl)pyrrolidine in the form of its dihydrochloride-salt, MP. 2524-2674 C. (decJ (corn),

Analysis.-Calcd. for C33H56I-I2O.2HC1: C. 69.57; H, 10.26; (:1, 12.4 Found: 3, 9.44; H, 10.56; or, 12.72.

10,1'0a-tetradecahydro 3,1021: ethenophenanthro[1,2-c]- 1'-[3-( l-pyrrolidyl)propyl]-2t,5'pyrro1idinedione (Example 5) and 5.69 g. of lithium aluminumhydride in 370.

, mlfof tetrahydrofuran according to the ,manipulative 4b,8 dimethyl 8 hydroxymethyl 12 isopropyl- 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetlf adecahydro 3,1{)aethenophenanthroflic]1-.1' '(3 hexamethyleniminopropyl)pyrrolidin'e in :the form of its dihydro'chloride salt. was found to have a'minimum effective hypotensive dose of about 0.10 mglkg. of body weight when injected subcutaneously into renal hypertensive rats and measured by the photoelectric footmethodof Kersten'et a1., loc cit.

' procedure described above inExample 27. The product was recrystallizedfrom aqueous methanol togive '1 1.90 '1 V g. of 4b,8dimethyhS-hydrbxymethyl}12-isopropyl-1,2,3,4, 4a,4b,5,6,7,8,8a,9,10,10a-tetradecahydro 3,102. -.ethenochloroform). I Y

Analysis-Calm. fOrC H N O: C, 79.43; H, 11.18;

N, 5.98. Found: c, 79.51; H, 10.98;N,16.'03.'

4b,8-dimethyl-8-hydroxymethyl 12 isopropyl-I1,2, 3,4,"

4a,4b,5,6,7,8,8a,9,10,10a-tetradecahydroe 3,10a ethenotimes that of papaverine when measured on the isolated rabbit heart by the method of Luduena et al. loc. cit.

EXAMPLE 31 4b,8-dimethyl-S-hydroxymethyl 12 isopropyl-1,2,3,4, 4a,4b,5,6,7,8,8a,9,10,10a-tetradecahydro 3,10a ethenophenanthro[1,2-c] 1 [2-(1-piperazinyl)ethyl]pyrrolidine [1; R is CH OH, X is H Y is CH CH N B is N(CH NH] can be prepared by reducing S-carboxy- 4b,8-dimethyl 12 isopropyl-l,2,3,4,4a,4b,5,6,7,8,8a,9, 10.10a-tetradecahydro-3,IOa-ethenophenanthro [1 .2-c]-1- [2-( l-piperazinyl) ethyl] -2',5'-pyrrolidinedione (Example 6) with lithium aluminum hydride according to the manipulative procedure described above in Example 26 or 27.

EXAMPLE 32 4b,8-dimethyl-B-hydroxymethyl 12 isopropyl-1,2,3,4, 4a,4b,5,6,7,8,8a,9,10,10a-tetradecahydro 3,10a ethenophenanthro[1,2-c] 1' [2-(4-phenyl 1 piperazinyl) ethyl]pyrrolidine [1; R is CH OH, X is H Y is CH CH N B is N(CH NC H was prepared from 11.19 g. of 8-carboxy-4b,8-dimethyl 12 isopropyl-1,2,3,4,4a,4b,5,6, 7,8,8a,9,10,l0a tetradecahydro 3,10a ethenophenanthro[1,2-c] 1 [2-( l-phenyl-1-piperazinyl)ethyl]-25- pyrrolidinedione (Example 7) and 3.61 g. of lithium aluminum hydride in 325 ml. of tetrahydrofuran according to the manipulative procedure described above in Example 27. The product was recrystallized from an ethyl acetate-petroleum ether (Skellysolve C) mixture and dried at 80-82 C. for twenty hours in vacuo to give 8.67 g. of 413,8-dirnethyl-S-hydroxymethyl-l2-isoproyl- 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,10aetheriophenanthro[l,2-c] 1 [2-(4 phenyl 1 piperazinyl)ethyl]-pyrrolidine, M.P. 124.8-128? C. (corr.), [a] =-l2..3. (1% in chloroform).

Analysis.-Calcd. for C H N O: N(tta1), 7.70; Nw FOUIldI Nfi t 7.65; Nw 4.87.

EXAMPLE 3 3 EXAMPLE 34 4b,8-dimethyl-s-hydroxymethyl 12 isopropyl-1,2,3,4, 4a,4b,5,6,7,8,8a,9,10,10a-tetradeca11ydro 3,10a ethenophenanthro[1,2-c] 1 (Z-di-n-butylaminoethyl)pyrrolidine [1; R is CH OH, X is H Y is CH CI-1 N B is N(C Hg)2] can be prepared by lithium aluminum hydride reduction of 8-carboxy-4b,8-dimethyl-12-isopropyl-1,2,3, 4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro-3,lOa-ethenophenanthr0[1,2-c] 1' (Z-di-n-butylaminoethyl)' 2',5'- pyrrolidinedione (Example 10) according to the manipulative procedures described above in Examples 26 and 27.

EXAMPLE 35 4b,8 dimethyl 8 hydroxymethyl 12 isopropyll,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,10aethenophenanthro[1,2 c] 1' (2 di n hexylaminoethyl) pyrrolidine [1; R is CH OH, X is H Y is CH CH N B is N(CH 1-1 can be prepared by lithium aluminum hydride reduction of S-carboxy-4b,8-dimethyl-12-isopropyl 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,109. ethenophenanthro[1,2 c] 1' (2 di nhexylaminoethyl) -2,5 -pyrrolidinedione (Example 1 1) according to the manipulative procedures described above in Examples 26 and 27.

1d EXAMPLE 36 4b,8 dimethyl 8 hydroxymethyl 12 isopropyl 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,10aethenophenanthro[1,2 c] 1 (2 dicyclohexylaminoethyl) pyrrolidine [1; R is CH OH, X is H Y is CHzCHg, N B is N(C ,H can be prepared by lithium aluminum hydride reduction of 8-carboxy-4b,8-dimethyl-12-isopropyl 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10atetradecahydro- 3,1021 ethenophenanthro[1,2 c] 1 (2 dicyclohexylaminoethyl)-2,5'-pyrrolidinedione (Example 12) according to the manipulative procedures described above in EX- amples 26 and 27.

EXAMPLE 37 EXAMPLE 38 4b,8 dimethyl 8 hydroxymethyl 12 isopropyl- 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,1021- ethenophenanthro[1,2 c] 1 (2 N methylcyclohexylaminoethyl)pyrrolidine [1; R is CH OH, X is H Y is CH CH N B is N(CH (G l-1 can be prepared by lithium aluminum hydride reduction of 8-carboxy-4b,8- dimethyl-lZ-isopropyl 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10atetradecahydro 3,10a ethenophenanthro[1,2 c] 1' (2 N methylcyclohexylaminoethyl) 2',5' pyrrolidinedione (Example 14) according to the manipulative procedures described above in Examples 26 and 27.

EXAMPLE 39 4b,8 dimethyl 8 hydroxymethyl 12 isopropyl- 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,102. tetradecahydro 3,10aethenophenanthro[1,2 c] 1' [2 (1 piperidyl)ethyl]- pyrrolidine [1; R is CH OH, X is H Y is CH CH N B is N(CH can be prepared by lithium aluminum hydride reduction of 8-carboxy-4b,8-dimethyl-12-isopropyl- 1,2,3,4,4a,4b,5,6,7,8,8a,9,l0,10a tetradecahydro 3,10aethenophenanthro[1,2 c] 1 [2 (1 piperidyl)ethyl]- 2,5-pyrrolidinedione (Example 15) according to the manipulative procedures described above in Examples 26 and 27.

EXAMPLE 4O 4b,8 dimethyl 8 hydroxymethyl 12 isopropyl- 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,1021- etheuophenanthro[l,2 c] 1' [2 (2 methyl 1 pyrrolidyl)ethyl]pyrrolidine [1; R is CHzOH, X is H Y is CH CH N B is Z-methyl-l-pyrrolidyl] can be prepared by lithium aluminum hydride reduction of 8-carboxy- 4b,8 dimethyl 12 isopropyl 1,2,3,4,4a,4b,5,6,7,8, 8a,9,10,10a tetradecahydro 3,10a ethenophenanthro- [1,2 c] 1 [2 (2 nethyl 1 pyrr0lidyl)ethyl]- 2',5-pyrrolidinedione (Example 16) according to the manipulative procedures described above in Examples 26 and 27.

4b,8 dimet y 8 hydroxymethyl 12 isopropyll,2,3,4,4a,4b,5,6,7,8,8a,9,lO,10a tetradecahydro 3,108.- ethenophenanthro[1,2 c] 1 [2 (4 methyl 1- piperazinyl)ethyl]pyrrolidine [1; R is CH OH, X is H Y is CH CH N B is N(CH NCH can be prepared by lithium aluminum hydride reduction of 8-catboxy-4b,8- dimethyl 12 isopropyl 1,2,3,4,4a,4b,5,6,7,8,8a,9,10, 10a tetradecahydro 3,10a ethenophenanthro[l,2 c]- 1' [2 (4 methyl 1 piperazinyl)ethyl] 2,5 pyramples 26 and 27.

I 26 and 27.

15 rolidinedione (Example 17) according to the manipulative procedures described above in Examples 26 and 27.

7 EXAMPLE 42 4b,8 dimethyl 8 hydroxymethyl 12 isopropyl- 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,10aethenophenanthro[l,2 1 (2 dibenzylaminoethyl)- pyrrolidine [1; R is CH GH, X is H Y is CH CH N 3 is N (CH C H can be prepared by lithium aluminum hydride reduction of 8-carboxy-4b,8-dimethyl-12-isopro-,

pyl 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro- 3,10a ethenophenanthro[1,2 c] 1.- (2 dibenzylami noethyl)-2,S'-pyrroiidinedione (Example 18) according to the manipulative procedures described above in EX- EXAMPLE 43 4b,8 dimethyl 8 hydroxymethyl l2 isopropyll,2,3,4,4a,4b,5,6,7,8,8a,9,10,1021 tetradecahydro 3,1621

ethenophenanthro[1,2 c] 1' [2 (2 phenylethyl)- aminoethylJpyrrolidine [1; R is CH OH, X is H ,"Y is CH CH N=B is N(CH CH C H can be prepared by lithium aluminum hydride reduction of 8-carboxy- 4b,8 --dimethyl 12 isopropyl l,2,3,4,4a,4b,5,6,7,8,

8a,9,l0,10a tetradecahydro 3,1021 ethenophenanthro- [1,2 c] 1' [2 bis(2 phenylethyl)aminoethyl]- V 2',5'-pyrrolidinedione (Example 19) according to the manipulative procedures described above in Examples EXAMPLE 44 4b,8 dimethyl 8 hydroxyrnethyl l2 isopropyl-- 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,10aethenophenanthro[l,2 c] l (2 N methylbenzylaminoethyl)pyrrolidine [1; R is CH OH, X is H Y is CH CH N=B is N(CH )(CH C H can be prepared by lithium aluminum hydride reduction of 8-carboxy-' 4b,8 dimethyl l2 isopropyl l,2,3,4,4a,4b,5,6,7,8, 8a,9,10,10a tetradecahydro -'3,l0a ethenophenanthro- [1,2 c] l (2 N methylbenzylaminoethyl) 2',5

pyrrolidinedione (Example 20) according to the manipulative procedures described above in Examples 26 and 27. j p

EXAMPLE 45 4b,8 dimethyl 8 hydroxymethyl l2 isopropyl- 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,1021 tetradecahydro 3,10aethenophenanthro[1,2 c] 1 (2 dimethylamino 1- methylethyDpyrrolidme [1; R is CHgOH, X is H Y is CH(CH )CH N=B is N(CH can be prepared by I Lithium aluminum hydride reduction of 8-carboxy-4b,8-

dimethyl l2 isopropyl 1,2,3,4,4a,4b,5,6,7,8,8a,9,10, 7 10a tetradecahydro 3,10a ethenophenanthro[l,2 c]- 1 (2 dimethylamino 1 methylethyl) 2,5' pyrrolirolidine [1; R is CH OH, X is Fi Y is CHZCHQCHQCHZ,

N=B is N(CH can be. prepared by lithium aluminum hydride reduction of 8-carboxy-4b,S-dimethyl-12- isopropyl l,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a-tetradecahydro- 3, l 0a-ethenophenanthro 1,2-c] 1 '-(4-dimethylaminobutyl)-2',5-pyrrolidenedione (Example 23) according to the manipulative procedures described above in Examples 26 and 27.

EXAMPLE 4s EXAMPLE 49 4b,8'- dirnethyl 8-hydroxymethyl-12-isopropyl-l,2,3,

4,4a,4b,5,6,7,8,8a,9,10,1021 tetradecahydro-F, IOa-ethenoA phenanthro[1,2-c] 1' (Z-dimethylamino LZ-dimethylethyDpyrrolidine [I; R is CH OH, X is -1 Y is CH(CH )CH(CH3), N=B is N(CH can be prepared by lithium aluminum hydride reduction of S-carboxy 4b,8 dimethyl-l2-isopropyl-1,2,3,4,4a,4b,5,6,7,8, 8a,9,l0,l0a tetradecahydro 3-,10a-ethenophenanthro [1,2-c] 1- -(2. dimethylamino-l,Z-dimethylethyl)-2',5

pyrrolidinedione (Example 25) according to the manipulative procedures described above in Examples 26 and 27.

c EXAMPLE so 4b,8 dimethyl 4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro-3,IOa-ethenodinedione (Example 21) according to the manipulative V procedures described above inExamples 26 and27.

EXAMPLE 46 H 4b,8 dimethyl 8 hydroxymethyl 12 isopropyl- 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a'- tetradecahydro 3,1021- i ethenophenanthro[1,2 c] 1 (2 dimethylaminopro- V V pyl)pyrrolidine [I; R is CH OH, X is Fi Y is cu cmon,

N=B is N(CH can be prepared by'lithium aluminum hydride reduction of 8-carboxy-4b,8-dimethyl-IZ-isopropyl 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,1021 tetradecahydroa 3,10a eth'enophenanthro[l,2 c] 7 l 7 (2 dimethyiamiriopropyD-Z', -pyrrolidinedioue (Example 22) accordingto the manipulative procedures described above in Examples 26 and 27, v EXAMPLE 47v Y 8 hydroxymethyb1 2-isopropyl-1,2,

7 3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro '3,10a

ethenophenanthro[1-,2-c] -'1'-(4-dimethylaminobuty1)pyrphenanthro[l,2-c] 1' (Z-diethylaininoethyl)-2',5,-pyrrolidinedione [1; R is CH OH, X is O, Y is CH CH N=B is N(C H can be prepared by rapidly adding a mix.

ture of 8-carbomethoxy-4b,S-dirnethyl-12-isopropyl- 1,2,3,

4,4a,4b,5,6,7,8,8a,9,10,1021 tetradecahydro-S,lOa-ethenophenauthro[1,2-c] l'- (2 diethylaminoethyl)-2',5 pyrrolidinedioue (Example 8). and ethyl alcohol to an excess of molten sodium, alone, or m an inert solventsuch' as toluene or xylene. The reactionmixture is vstirred vigorously until the reaction has ceased, the excesssodium carefully decomposed by adding ethanol, and the product isoiated by filtration oi extraction.

' EXAMPLE 51 8 carboxy 4b,8-dimethyl-12-is0propyl-1,2,3,4,4a,4b, 5,6,7,8,8a,9,10,10a tetradecahy-dro-3,10a-ethen0phenanthro[l,2-c] 1" (2-diethylaminoethyl)-2',5'-pyrrolidinedione (Example 1) can be caused to react with thionyl chloride to give the corresponding acid chloride. The latter then can be caused to react with sodium borohydride to give '4b,8-dimethyl-S-hydroxymethyl-12-isopropyl 1,2,3,4,4a,4b,5,6,7,8,8a,9,l0,1Ga tetradecahydro- 3,10a ethenophenanthro[1,2-c] 1-(2-diethylaminoeth product as obtained;

yl)-2',5-pyrrolidinedione, the same above in Example 50.

EXAMPLE 52 8 carboxy 4b,8-dimethyl-12-isopropyl 1,2,3,4,4fl,4 5,6,7,8,8a,9,10,l0a tetradecahydro 3,10a-ethenophen anthro[1,2-c]-1'-(2-diethylaminoethyl) yrrolidine [1; R.

can be prepared by vigorously stirring at room temperature a mixture of 4b,8dimethyl 8-hydroxymethyl-l2-isopropyl 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahy- V dro 3,1021 ethenophenanthro[1,2-c]-1'-(Z-diethylaminm ethyl) pyrrolidine (Example 26) and chromic acid in sul-v furic acid solution. The product is isolated by filtration or extraction in the usual manner. I

S-hydroxyinethyl-l2-isopropyl-l,2,3, V

17 EXAMPLE s3 8 carbomethoxy 4b,8-dimethyl-12-isopropy1-l,2,3, 4,4a,4b,5,6,7,8,8a,9,10,10a tetradecahydro-3,10a-ethenophenanthro[1,2-c] 1-(2-diethylaminoethyl)pyrrolidine [1; R is COOCH X is H Y is CH CH N=B is N(C H can be prepared by causing 8-carboxy-4b,8- dimethyl 12-isopropyl-1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10atetradecahydro 3,10aethenophenanthro[1,2-c]-1'-(2-diethylaminoethyl)pyrrolidine (Example 52) to react with an ethereal solution of diazomethane.

wherein R represents carboxy; X represents 0, Y represents lower-alkylene; and N=B represents di-lower alkylamino. a

2. A compound of the formula wherein R represents carboxy; X represents Y represents lower-alkylene; and N=B represents polymethylenimino having from to 7 ring members.

3. A compound of the formula wherein R represents hydroxymethyl; X represents H Y represents lower-alkylene; and N=B represents dilower-alkylamino.

4. A compound of the formula wherein R represents hydroxymethyl; X represents H Y represents lower-alkylene; and N=B represents polymethylenimino having from 5 to 7 ring members.

5. 8 carboxy 4b,8-dimethyl-12-isopropyl-1,2,3,4,4a, 4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,10a-ethenophenanthro[1,2-c] 1 (Z-diethylaminoethyl)-2,5-pyrrolidinedione.

6. 8 carboxy 4b,8 dimethyl-12-isopropy1-1,2,3,4, 4a,4b,5,6,7,8,8a,9,10-10a tetIadecahydm-BJOa-ethenQ- phenanthro 1,2-c] -1'- [2- (4-morpholinyl) ethyl] -2,5'-pyrrolidinedione.

7. 8 carboxy-4b,8-dimethyl-12-isopropyl-1,2,3,4,4a, 4b,5,6,7,8,8a,9,10,10a tetradecahydro 3,1021 ethenophenanthro[1,2-c] 1' (3-hexamethyleniminopropyl)- 2,5'-pyrrolidinedione. t

8. S-carboxy 4b,8 dimethyl-l2-isopropyl-1,2,3,4,4a, 4b,5,6,7,8,8a,9,10,10a-tetradecahydro 3,10a ethenophenanthro[1,2-c] 1' (B-dhnethylaminopropyl)-2,S'-pyrrolidinedione.

9. S-carboxy 4b,8 dimethyl-12-isopropyl-1,2,3,4,4a, 4b,5,6,7,8,8a,9,10,10a-tetradecahydro 3,103. ethenophenanthro 1,2-c] -1'-[3-(1 pyrrolidyl)propyl] -2,5'-pyrro1idinedione.

10. 8-carboXy-4b,8-dimethyl-12-isopropyl-1,2,3,4,4a,4b, 5,6,7,8,8a,9,10,10a-tetradecahydro 3,10a ethenophenanthro[ 1,2-c] -1-[2-( 1 piperazinyl ethyl] -2',5-pyrrolidinedione.

l 1. 8-carboXy-4b,8-dimethy1-12-isopropyl-1,2,3 ,4,4a,4b, 5,6,7,8,8a,9,10,10a-tetradecahydro 3,10a ethenophenanthro[1,2-e] 1' [2-(4-phenyl-1-piperazinyl)ethyl]-2',5'- pyrrolidinedione.

l2. 4b,8 dimethyl-S-hydroxymethyl-12-isopropy1-1,2, 3,4,4a,4b,5,6,7,8,8a,9,10,10a-tetradecahydro-3,IOa-ethenophenanthro[1,2-c]-1'-(Z-diethylaminoethyl)pyrrolidine.

13. 4b,8 dimethyl-S-hydroxymethyl-12-isopropyl-1,2, 3,4,4a,4b,5,6,7,8,8a,9,10,10a-tetradecahydro-3, IOa-ethenophenanthro[l,2-c] 1' [2-(4-morpholinyl)ethyl]pyyrolidine.

14. 4b,8 dimethyl-S-hydroxymethyl-12-isopropyl-1,2, 3,4,4a,4b,5,6,7,8,8a,9,1 0,10a-tetradecahydro-3,10a1ethenophenanthro[1,2-c]-1-( 3 hexamethyleniminopropynpyrrolidine. v .t I

15. 4b,8-dimethyl-8 hydroxymethyl-l2-isopropy1-1,2,3, 4,4a,4b,5,6,7,8,8a,9,10,10a-tetradecahydro 3,102. etheno phenanthro[1,2-c] 1' (3 dimethylaminopropyl)pyrrolidine.

16. 4b,8 dimethyl-8-hydroxymethy1-12-isopropy1-1,2, 3,4,4a,4b,5,6,7,8,8a,9,10,10a-tetradecahydro-3,10a-ethenophenanthro[1,2-c] 1 [3-(l-pyrrolidyl)propyl]pyrrolidine.

17. 4b,8 dimethyl-S-hydroxymethyl-12-isopropyl-1,2, 3,4,4a,4b,5,6,7,8,8a,9,l0,10a-tetradecahydro-3,lOa-ethenophenanthro[1,2-c] 1' [2-(4-pheny1-1-piperazinyl)ethyl] pyrrolidine.

18. A member of the group consisting of compounds of the formula wherein R represents a member of the group selected from carboxy, carbo-lower-alkoxy, hydroxymethyl and carboxylic acyloxymethyl; X represents a member of the group selected from H and O; Y represents lower-alkylene; and N=B represents a member of the group consisting of di-loWer-alkylamino, dicycloalkylamino in which the cycloalkyl has from 5 to 6 ring members, N-(cycloalkyD-N-lower-alkylarnino in which the cycloalkyl has from 5 to 6 ring members, polymethyleneimino having from 5 to 7 ring members, 4-morpho1inyl, l-piperazinyl, 4-hydrocarbon-l-piperazinyl in which the hydrocarbon has from 1 to 10 carbon atoms, di-(phenyl-lower-alkyhamino, and N-(phenyl-lower-alkyl)-N-lower-alkylamino and acid-addition salts and lower-alkyl, lower-alkenyl and 19 monocarbocyclic aryl lower-alkyl quaternary ammonium salts thereof. 7 J

19. The process for preparing a compound of the formula i CH R wherein R represents a member of the group selected from carboxy and carbo-lower-alkoxy; Y represents lower-a1- kylen'e; and N=B represents a memberof the group consisting of di-lower-alkylamino, dicycloalkylamino in which the cycloalkyl has from 5 to 6 ring members, N-(cycloalkyD-N-lower-alkylamino in which the cycloalkyl has 7 from 5 to 6 ring members, polymethyleneimino having from 5 to 7 ring members, 4-rnorpho1inyl, l-piperazinyl,

'4-hydrocarbon-l-piperazinyl in which the hydrocarbon has from 1 to 10 carbon atoms, di- (phenyl-lower-alkyl)amino, and N-'(phenyl-'lower-alkyl)-N-lower-alkylamino, which comprises reacting a member of the group consisting of maleopimaric acid and 'lower alkyl esters thereof with a "compound having the formula H N-Y--N:B.

20. The process for preparing a compound of the formula wherein R represents a member of the group selected from carboXy and carbo-lower-alkoxy, and Y and N=B have the meanings given above, with lithium aluminum hydride.

References Cited in the file of, this patent UNITED STATES PATENTS Fleck Oct. 1'0, 1944 Mannheimer Feb. 12, 1957 OTHER REFERENCES Gaylor: Reduction With Complex Metal Hydrides (1956), Interscience Publishers, Inc., New York.

UNITED STATES PAlENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 l35 749 June 2 1964 Raymond 0., Clinton et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column i line 2O for "The" read They line 67,, for sulfonic" read sulfuric column 8 line 34 for "L is" read Y is column 9 line T for "dimethylaminopyroply" read dimethylaminopropyl line ll for dimethylaminopyropylamine" read dimethylaminopropylamine column 14, between lines 66 and 67, insert EXAMPLE 41 column 15, line 20, for [2(2phenylethyl)" read [2-bis(2phenylethyl) Signed and sealed this 3rd day of November 1964.,

(SEAL) Attest:

ERNEST W9 SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

18. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA 